Left-sided (distal) ulcerative colitis and ulcerative proctitis are disease subtypes of ulcerative colitis with multiple treatment options. In addition to oral formulations used in patients with extensive colitis or pancolitis, those with disease limited to the distal 60 cm from the anal verge also have the option of topical rectal therapies with aminosalicylates or glucocorticoid formulations [R. D. Cohen et al. The American Journal of Gastroenterology; Vol. 95, No. 5, 2000; p. 1263]. Suitable dosage forms for rectal delivery include suppositories, foams and liquid enemas, which differ with respect to their physiochemical properties and potential for proximal spread. A randomized prospective comparison of foams versus liquid enemas reported that patients preferred the foam because of greater comfort, ease of retention and minimal interference with their daily routine. The disadvantage of using foams instead of liquid enemas is the decreased proximal spread of the foam. Whereas liquid enemas have been shown to extend reliably as far as the splenic flexure, the foam can only reach the proximal sigmoid colon [J. K. Marshall of al. The American Journal of Gastroenterology; vol. 95, No. 7, 2000: p. 1628]. Especially when the rectal treatment involves the use of the sparingly absorbed and hence locally-acting prednisolone metasulphobenzoate, the efficacy of the therapy is dependent upon direct contact of this active ingredient with the inflamed mucosa. Hence it is important that a highly expanded volume of the foam is obtained in order to provide wide distribution throughout the diseased area.
It is known to use aqueous foams having a highly expanded volume. An example of such foam comprising prednisolone metasulphobenzoate is known from EP0774957. This patent teaches that an increased spreading of the active pharmaceutical along the intestine can be obtained by using a composition that exhibits a delayed foaming action. Such delayed foaming may be achieved by providing a composition in a pressurised container wherein the propellant is physically separated from said composition. However, the disadvantage of this single-dosage foaming composition is that although a highly expanded volume of the foam of up to 275 ml may be obtained, the initial volume of the unfoamed composition to be dosed is also extremely high (22 ml). Such high initial volume is disadvantageous since it requires the use of a large canister, especially when multiple doses are to be contained in said canister. The packaging and distribution of large canisters is an economic disadvantage. Furthermore, such large canister is very impractical to handle for the patient.
From the prior art compositions it appears that aerosol foams are complicated physical-chemical structures that do not form under arbitrary circumstances. In particular, a special balance between the foam-forming components is important. Slight shifts in the composition may already result in a collapse of the foam or alternatively the foam is not formed at all, especially when administration is to occur via an applicator nozzle with small diameter. Thus, a given formulation may not simply be adapted without further provisions to result in the desired foam. Especially, the problem with highly expandable foam-forming compositions according to the prior art is that due to their appearance preliminary ejection of said formed foam is easily induced. This results in insufficient retention of the active ingredient to the mucosa of the inflamed area which is necessary to obtain optimal results in combating the disease.
Hence, it is an object of the present invention to provide a foam-forming composition for prednisolone and its derivatives that solves the problems identified above.
Surprisingly, we have now found that an increased volume expansion ratio of the foam has a major effect on the appearance of the formed foam and hence provides an advantageous and clinically improved composition that may serve as an alternative for the few compositions that are currently available on the market.